Derivatives of 1h-2, 1, 3-benzothiadiazin-4(3h)-one 2-oxide and intermediates therefor



United States Patent 3,217,001 DERIVATIVES 0F 1H 2,1,3 BENZOTHIADIAZIN- 4(3H) ONE 2 OXIDE AND INTERMEDIATES THEREFOR Arthur A. Santilli, Ardmore, and Thomas S. ()sdene, Berwyn, Pa., assiguors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Aug. 19, 1963, Ser. No. 303,155 10 Claims. (Cl. 260-243) This invention is concerned with therapeutically active derivatives of lH-2,l,3-benzothiadiazin-4(3H)-one 2- oxide and with novel aminobenzamides which occur as intermediates in the preparation of such derivatives. These compounds exert a psycholeptic action on the central nervous system.

The compounds of this invention may be characterized as having a 11-1 2,1,3 benzothiadiazin 4(3I-I) one 2-oxide nucleus to which is attached: in the 1-position, a lower alkyl group; in the 3-position, a lower alkyl, an halo(1ower)alkyl, an alkoxyalkyl, a phenyl(lower)alkyl, an halophenyl(lower)alkyl, or a cycloalkyl group and optionally, in the 6-position, a hydrogen atom, a halogen atom, a nitro group, or a lower alkylsulfamoyl group.

Preferred compounds in accordance with the present invention are represented by the following general formula:

wherein R'is lower alkyl preferably having from 1 to 4 carbon atoms in the alkyl chain, halo(lower)alky1 preferably having from 1 to 4 carbon atoms, lower alkoxy (lower) alkyl preferably having from 1 to 4 carbon atoms, phenyl(lower)alkyl preferably having from 1 to 4 carbon atoms in the alkyl chain, halo phenyl(lower)alkyl preferably having from 1 to 4 carbon atoms in the alkyl chain, or a cycloalkyl group preferably having up to 6 carbon atoms; X is hydrogen, chlorine, nitro, or a lower alkylsulfamoyl group preferably having up to 2 carbon atoms in the alkyl chain; R is lower alkyl preferably having from 1 to 4 carbon atoms. As employed herein, the term alkyl refers both to the normal and the branched chain radicals.

The intermediates which occur in the synthesis of the present compounds may be characterized as having a 2-(lower)alkyl-aminobenzamide nucleus having attached thereto, in the -position, a hydrogen atom, a halogen atom, a nitro group or a lower alkylsulfamoyl group; on the nitrogen atom of the amido group, a lower alkyl group, a halo(lower)alkyl, an alkoxyalkyl, a hydroxyalkyl, a phenyl(lower)alkyl, an halo phenyl(lower) alkyl group or a cycloalkyl group. These intermediates are represented by the structural formula:

II E

wherein X and R are as defined under Formula I, above,

and R encompasses the same substituents as R above,

and additionally represents an hydroxy(lower)alkyl radical preferably having up to 4 carbon atoms. In the course of the reaction leading to the final products this substituent is chlorinated by the reagent used therein.

The compounds of this invention are prepared by amidating in an equeous or alcoholic solvent'or in a mix- 3,217,001 Patented Nov. 9, 1965 ture of such solvents a N-(lower) alkyl isatoic anhydride (III) of the formula:

where X and R are as above, with a primary amine of the formula (IV) R NH where R, is as above defined, to form the intermediate benzamide (II). The latter compound is then refluxed with excess thionyl chloride for one to three hours. Removal of the excess thionyl chloride affords the desired product (I). This sequence of reactions may be represented schematically as follows:

0. t O H X- X- -iiNR1 5 O +R1NHz NH N \N SeO (I) The following specific examples serve to illustrate but are not intended to limit the present invention.

Example 1 To a solution of 3.1 g. of ethanolamine in 40 ml. of ethanol was added 10.5 g. of 6-ch'loro-N-methylisatoic 'anhydride. The reaction mixture was warmed for a few minutes on the steam bath. After the evolution of carbon dioxide was complete, the solvent was removed on a rotary evaporator. The oily residue crystallized to a solid mass on cooling and amounted to 6.7 g., M.P. 1-l6122. Recrystallization from benzene afforded 5-chloro-N-(2-hydroxyethyl)-2-methylaminobenzamide, M.P. 125 .5129.

Analysis.Calculated: C=52.53, H=5.73, N=12.25, Cl=15.51. Found: C=52.60, H=5.51, N=12.53, Cl: 15.51.

When tested pharmacologically, this compound exhibited analgesic, diuretic, anticonvulsant, and anti-tremorine activities.

Example 2 To 50 ml. of 33% aqueous ethylamine solution was added 5.2 g. of 6-chloro-N-methylisatoic anhydride. After warming for a few minutes on the steam bath, the evolution of carbon dioxide ceased. The reaction mixture was allowed to stand an additional hour at room temperature. The crystalline material which deposited out of solution amounted to 5.2 g., M.P. 109112. Recrystallization from cyclohexane gave S-chloro-N-ethyl-Z- methylaminobenz amide, M.P. 96.5.'

Analysis.Ca1culated: C=56.47, H=6.16, N=13.17, Cl=16.67. Found: C=56.58, H=6.06, N==l3.30, CI: 16.4.

When tested pharmacologically, this compound exhibited analgesic, anti-metrazol and anti-tremorine activities.

Example 3 To a solution of 7.1 g. of o-chlorobenzylamine in 50 ml. of ethanol was added 11.5 g. of 6-chloro-N-methylisatoic anhydride. The reaction mixture was heated on the steam bath until the evolution of carbon dioxide ceased, and complete dissolution of solids was attained. The reaction mixture was filtered. A white crystalline product was deposited out of solution which amounted to 9.9 g., M.P. 133-6. Recrystallization of the product from ethanol afforded 5-chloro-N-(o-chlorobenzyl)-2- methylaminobenzamide, M.P. 137.5-139.

Analysis-Calculated: =58.27, H:4.56, N:9.06, 01:22.93. Found: 0:58.54, H:4.41, N:8.77, 01: 22.5.

Example 4 'To a solution of 4.5 g. of 2-ethoxyethylamine in 50 ml. of ethanol was added 11.5 g. of 6-chloro-N-methylisatoic anhydride. After the evolution of carbon dioxide had abated, the reaction mixture was heated for an additional 5 minutes on the steam bath. The solvent was removed on a rotary evaporator. The residual oil crystallized on standing in the cold room. The product, which amounted to 13.0 g., M.P. 50-63", was recrystallized from cyclohexane affording 5-chloro-N-(2-ethoxyethyl)-2-methylaminobenzamide, M.P. 73.4.

I Analysis.0alculated: 0:56.14, H:6.67, N=10.91, 01:13.81. Found: 0:55.90, H=6.47, N:l1.05, 01: 13.86.

When tested pharmacologically, this compound exhibited analgesic, anticonvulsant and central nervous system depressant activities.

Example 5 T o a solution of 9.68 g. of phenethylamine in 50 ml. of ethanol was added 15.9 g. of 6-chloro-N-methylisatoic anhydride. A brisk evolution of carbon dioxide occurred after warming for a few minutes on the steam bath. When gas evolution had abated, the reaction mixture was heated to the boiling point until dissolution of the solids had occurred. The reaction mixture was filtered. A white crystalline product was deposited out of solution. This on removal amounted to 16.0 g., M.P. 126-131. The product was recrystallized from ethanol afiording 5- chloro 2 methylamino N phenethylbenzamide, M.P. 132-4".

Analysis.-Calculated: 0:66.54, H:5.93, N:9.70, 01:12.27. Found: 0:66.41, H:5.90, N:9.73, 01: 12.3.

Example 6 .To a solution of 6.4 g. of cyclopentylamine in 40 m1. of ethanol was added 15.9 g. of 6-chloro-N-methylisatoic anhydride. The reaction mixture was heated for a few minutes on the steam bath until the evolution of carbon dioxide was completed. The solvent was removed on the rotary evaporator. The solid residue amounted to 16.5 g., M.P. 59-85. Recrystallization of the product from cyclohexane afforded 5-chloro-N-cyclopentyl-2-methylaminobenzamide, M.P. 153-5.

Analysis-Calculated: 0:61.77, H:6.78, N=l1.08, 01:14.03. Found: 0:61.50, H:6.74, N=11.36, Cl: 13.9.

Example 7 To a solution of 3.1 g. of 2-hydroxyethylamine in 40 ml. of ethanol was added 11.1 g. of 6-nitro-N-methylisatoic anhydride. After the evolution of carbon dioxide was complete, the reaction mixture was heated on the steam bath for a few minutes. The yellow crystalline product which separated was removed by filtration. The product weighed 9 g., M.P. 160-5". Recrystallization from ethyl acetate afforded N-(Z-hydroxyethyl)-2-methylamino-S-nitrobenzamide, M.P. 173-4.

Analysis.-Calculated: 0:50.20, H:5.45, N:15.57 Found: 0: 49.94, H:5.42, N:15.70.

When tested pharmacologically, this compound exhibited analgesic, anticonvulsant and central nervous system depressant activities.

Example 8 To a solution of 8.6 g. of o-chlorobenzylamine in 40.

ml. of ethanol was added 10.6 g. of N-methylisatoic anhydride. The reaction mixture was heated on the steam bath for 15 minutes and then filtered. A white crystalline product was deposited out of solution and amounted to 12.7 g., M.P. 132-3. The product was recrystallized from ethanol afiording N-(o-chlorobenzyl)-2-methylaminobenzamide, M.P. 133-134".

Analysis.0alculate: 0:65.58, H:5.50, N:10.20, 01:12.91. Found: 0:65.26, H:5.43, N:10.20, 01:13.0.

When tested pharmacologically, this compound exhibited analgesic activity.

Example 9 Example 10 A solution of 3.4 g. of 5-chloro-N-ethyl-2-methy1aminobenzamide in 40 ml. of thionyl chloride was boiled under reflux for 1 hour. The excess thionyl chloride was removed in vacuo on a rotary evaporator. The oil residue crystallized on cooling to give 3.9 g. of product, M.P. 89-92. The product was recrystallized from ethanol giving 6-chloro-3-ethyl-l-methyl-lH-Z,1,3-benzothiadiazin- 4(3H)-one 2-oxide, M.P. -96.5.

Analysis.-0alculated: 0:46.42, H:4.28, N:10.83, 01:1370, 5:12.39. Found: 0:46.62, H:4.43, N:10.73, 01:13.7, S: 12.3.

When tested pharmacologically, this compound exhibited analgesic, anti-convulsant, anti-tremorine and central nervous system depressant activities.

Example 11 A solution of 9.3 g. of S-chloro-N-(o-chlorobenzyl)-2- methylaminobenzamide in 45 ml. of thionyl chloride was heated under reflux for 2 hours. The excess thionyl chloride was removed in vacuo on a rotary evaporator. The solid residue amounted to 10.8 g., M.P. 142-5 Recrystallization from ethanol aiforded 6-chloro-3-(o-chlorobenzyl) l-methyl-1H-2,l,3-benzothiadiazin-4(3H)-one 2-oxide,,M.P. 148-1495".

Analysis.-0alculated: 0:50.71, H:3.40, N:7.89, 01:19.96, 5:9.03. Found: 0:50.85, H:3.49, N=7.89, 01:19.7, 8:8.8.

Example 12 A solution of 5.3 g. of S-chloro-N-(2-ethoxyethyl)-2- methylaminobenzamide in 25 ml. of thionyl chloride was boiled under reflux for 1 hour. The excess thionyl chloride was removed in vacuo on a rotary evaporator. The oily residue crystallized to a gummy solid weighing 6.2 g. Recrystallization of the product from cyclohexane afforded 6 chloro-3-(Z-ethoxyethyl)-1-methy1-1H-2,1,3-benzothiadiazin-(4(3H)-one-2-oxide, M.P. 73-4".

Analysis.Calculated: 0:47.60, H:4.99, N:9.25, 01:11.71, S:10.59. Found: 0:47.38, H:4.98, N:9.32, 01:11.71, S:10.2.

Example 13 A solution of 11 g. of 5-chloro-2-methylamino-N- phenethylbenzarnide in 40 ml. of thionyl chloride was boiled under reflux for 1 hour. The excess thionyl chloride was removed in vacuo on the rotary evaporator. The solid residue amounted to 13.0 g., M.P. 118123. The compound was recrystallized from ethanol alfording 6- chloro l methyl-3-phenethyl-1H-2,1,3-benzothiadiazin- 4(3H)-one 2-oxide, M.P. 127128.5.

Analysis.Calculated: C:57.57, H:4.23, N:8.39,

Cl=10.62, 8:9.60. Found: :57.50, H:4.45, N:8.21, Cl:10.82, S:9.53.

Example 14 A solution of 5.2 g. of 5-chloro-N-cyclopentyl-2-methylaminobenzamide in 30 ml. of thionyl chloride was boiled under reflux for 2 hours. The excess thionyl chloride was removed in vacuo on a rotary evaporator. The oily residue crystallized on cooling to a solid, weighing 5 g. Recrystallization from cyclohexane afforded 6 chloro-3-cyclopentyl-1-methyl-1H2,1,3 benzothiadiazin- 4(3H)-one-2-oxide, M.P. 1279.

Analysis.Calculated: (3:52.25, H:5.05, N:9.38, Cl:1l.87, 8:10.73. Found: 0:52.49, H:5.12, N:9.32, Cl:11.84, S:10.8.

Example A solution of 4 g. of N-(Z-hydroxyethyl)-2-methylamino5-nit-robenzamide in ml. of thionyl chloride was boiled under reflux for 2 hours. The excess thionyl chloride was removed in vacuo on a rotary evaporator. The solid residue amounted to 3.4 g., M.P. 145-50". Recrystallization from aqueous 2-ethoxyethanol afforded 3- (Lchloroethyl)-1-methyl-6-nitro-1H 2,1,3 benzothiadiazin-4(3H)-one-2-oxide, M.P. 16l-162.

Analysis.Calculated: C=39.54, H:3.32, N=13.84, Cl:11.67, 8:10.56. Found: C:39.69, H:3.25, N:13.68, Cl:11.85, S=10.1.

When tested pharmacologically, this compound exhibited analgesic activity.

Example 16 The reaction between 8.7 g. of N-(o-chlorobenzyl)-2- methylaminobenzamide and 40 ml. of thionyl chloride as in Example 9 affords 3-(o-chlorobenzyl)-1-methyl-1H 2,1,3-benzothiadiazin-4(3H)one-2-oxide.

Example 17 The reaction between 50 ml. of 33% aqueous ethylamine solution and 5.65 g. of 6-chloro-N-ethylisatoic anhydride aflords 5-chloro-N-ethyl-2-ethylaminobenzamide.

Example 18 The reaction between 4.5 g. of S-chloro-N-ethyl-Z-ethylaminobenzamide with 40 ml. of thionyl chloride as in Example 9 affords 6-chloro-1,3-diethyl-1H-2,1,3-benzothiadiazin-4(3H)-one-2-oxide.

Example 19 A solution of 26.5 g. of N-methylisatoic anhydride in 70 ml. of chlorosulfonic acid was heated for 1 hour on the steam bath, cooled and poured onto ice. The solid which separated was removed by filtration and was washed several times with water. The solid was added to 75 ml. of 33% aqueous ethylamine and then heated on the steam bath for 15 minutes. After cooling the reaction mixture, there was obtained 29.5 g. of product, M.P. -105 Recrystallization from aqueous ethanol afforded N-ethyl- S-ethylsulfamoyl 2 methylaminobeuzamide, M.P. 118- 120.

Analysis.Calculated: C=50.51, H:6.71, N=14.72, S:11.24. Found: 0:50.31, H:6.47, N: 14.76, S:1 1.4.

The compounds of this invention can be administered with pharmaceutically acceptable inert carriers in a wide. variety of oral or parenteral unit dosage forms containing from 5 to 500 mg. of active ingredients for the symptomatic adjustment of the dosage to the individual patient, or in admixture with other active compounds.

The present invention also includes the process of bringing the compounds thereof into a form suitable for therapeutic administration by associating them with liquid or solid, pharmaceutically acceptable carriers.

What is claimed is: 1. A compound having a 1H-2,1,3-benzothiadiazin-4- (3H)-one 2-oxide nucleus, said nucleus having attached thereto:

in the 1-position: a lower alkyl group; in the 3-position: a member of the group consisting of lower alkyl, halo (lower)a1kyl, (lower)a1koxy (lower) alkyl, phenyl and halophenyl(lower)alkyl and cycloalkyl having up to six carbon atoms in the ring;

in the 6-position: a member selected from the group consisting of hydrogen, halogen, nitro, and (lower)- alkylsulfamoyl.

2. 6 chloro 3 (2 chloroethyl) 1 methyl 1H- 2,1,3-benzothiadiazine-4(3H)-one 2-oxide.

3. 6 chloro 3 ethyl 1 methyl 1H 2,1,3 benzothiadiazin-4(3H)-one 2-oxide.

4. 6 chloro 3 (o chlorobenzyl) 1 methyl 1H- 2, 1 ,3-benzothiadiazine-4 (3H) -one 2-oxide.

5. 6 chloro 3 (2 ethoxyethyl) 1 methyl 1H- 2,1,3-benzothiadiazin-4(3H)-one 2-oxide.

6. 6 chloro 1 methyl 3 phenethyl 1H 2,1,3- benzothiadiazin-4(3H)-one 2-oxide.

7. 6 chloro 3 cyclopentyl 1 methyl 1H 2,1,3- benzothiadiazin-4(3H)-one Z-oxide.

8. 3 (2 chloroethyl) 1 methyl 6 nitro 1H- 2,l,3-benzothiadiazin-4(3H)-0ne 2-oxide.

9. 3 ethyl 6 ethylsulfamoyl 1 -methyl 1H 2,1,3- benzothiadiazin-4(3H)-one 2-oxide.

10. The process which comprises reacting in an alcoholic solvent a N-(lower)alkylisatoic anhydride of the formula:

wherein X is selected from the group consisting of hydrogen, halogen lower alkylsulfamoyl and nitro and R is a lower alkyl group; with a primary amine of the formula:

R NH wherein R is selected from the group consisting from (lower)alkyl, halo(lower) alkyl, hydroxyalkyl alkoxyalkyl, (lower)alkoxy, aralkyl, halo aralkyl and cycloalkyl to form a Z-aIkyIamino-beuzamide of the formula:

wherein X, R and R are as above stated; and further reacting said latter compound with thionyl chloride to form a compound of the formula:

References Cited by the Examiner UNITED STATES PATENTS 2,624,729 1/ 5 3 Melamed, et a1 260243 5 2,671,805 3/54 Krimmel 260558 0 3,006,916 10/ 61 Winthrop et a1. 260243 A 3,041,336 6/62 Teufel et al 260243 X 3,063,995 11/62 Bernstein et al 260243 3,066,167 11/62 Horrorn 260558 10 OTHER REFERENCES German printed application, S.N. 1,091,120, October Cohen et a1.: I.A.C.S. 84, 1995-2002.

from the group consisting of (lower) alkyl, halo(lower)- 15 WALTER A. MODANCE, Primary Examiner.

wherein X and R are as above stated and R is selected alkyl, alkoxyalkyl, aralkyl, halo aralkyl and cycloalkyl.

NICHOLAS S. RIZZO, Examiner. 

1. A COMPOUND HAVING A 1H-2,1,3-BENZOTHIADIAZIN-4(3H)-ONE 2-OXIDE NUCLEUS HAVING ATTACHED THERETO: IN THE 1-POSITION: A LOWER ALKYL GROUP; IN THE 3-POSITION: A MEMBER OF THE GROUP CONSISTING OF LOWER ALKYL, HALO (LOWER)ALKYL, (LOWER)ALKOXY (LOWER)ALKYL, PHENYL- AND HALOPHENYL(LOWER)ALKYL AND CYCLOAKYL HAING UP TO SIX CARBON ATOMS IN THE RING; IN THE 6-POSITION: A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, HALOGEN, NITRO, AND (LOWER)ALKYLSULFAMOYL. 